CRISPR-Cas9 疗法在癌症和遗传性基因病中的临床转化
Clinical translation of CRISPR-Cas9 therapeutics in cancer and inherited genetic disorders
CRISPR-Cas9是一种可编程的基因编辑工具，通过向导RNA把Cas9蛋白带到特定基因组位置进行切割。这篇综述系统检索文献和临床试验注册库，总结其在肿瘤和遗传病中的应用：编辑BCL11A增强子可重新激活胎儿血红蛋白，使多数可评估的镰状细胞病患者在预设期内未出现严重血管闭塞危象，多数输血依赖型β地中海贫血患者实现持续不输血；脂质纳米颗粒递送可在体内降低转甲状腺素蛋白水平；视网膜下注射腺相关病毒递送的编辑疗法使部分CEP290相关失明患者视功能改善。作者同时指出脱靶突变、染色体大片段重排、针对Cas9和病毒载体的免疫反应、肝外组织递送困难，以及生殖系编辑伦理和高昂费用等转化障碍。
为什么推荐给您：系统综述已有基因编辑临床证据，属于对成熟领域的梳理，无新数据。
不需要生物学背景，多打比方
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摘要Abstract
CRISPR-Cas9, adapted from the bacterial Type II CRISPR adaptive immune system, functions as a programmable RNA-guided endonuclease that employs a single-guide RNA to direct Cas9 to specific genomic loci. CRISPR-Cas9 has transformed targeted genome editing by replacing complex protein engineering with programmable Watson-Crick base pairing between the guide RNA and target DNA. This review was developed following a structured literature search of major biomedical databases and clinical trial registries to synthesize current evidence on the therapeutic applications of CRISPR-Cas9 in oncology and inherited genetic disorders. Clinical studies of ex vivo BCL11A-enhancer editing have shown fetal hemoglobin reactivation, with most evaluable participants with sickle cell disease remaining free of severe vaso-occlusive crises for the prespecified period and most evaluable participants with transfusion-dependent β-thalassemia achieving sustained transfusion independence. In vivo reductions in circulating transthyretin protein levels have been achieved for transthyretin amyloidosis via lipid nanoparticle delivery, while clinically meaningful improvements in selected measures of visual function were observed in a subset of patients receiving subretinal AAV-delivered CRISPR editing for CEP290-associated Leber congenital amaurosis type 10. Preclinical and early clinical studies have further investigated CRISPR-engineered T cells designed to improve antitumor activity, persistence, or resistance to inhibitory signaling. Despite these advances, key translational hurdles include the risk of off-target mutations and large-scale chromosomal rearrangements. Furthermore, immune responses against bacterial Cas9 nucleases and viral delivery vectors may limit the long-term efficacy of CRISPR-based therapies, while technical barriers surrounding delivery to extrahepatic tissues, such as skeletal muscle and the central nervous system, continue to hinder broader clinical success. Ethical concerns regarding germline modifications and the high cost of individualized therapies present additional translational challenges. Consequently, emerging DSB-independent technologies, such as base editing and prime editing, may reduce selected DSB-associated liabilities, but each introduces distinct editing, delivery, and genotoxicity risks that require product-specific evaluation.